Cu ions induce yeast metallothionein gene transcription by altering the conformation and DNA binding activity of the ACE1 transcription factor. We have proposed that the amino-terminal domain of ACE1 forms a polynuclear Cu(I)-S cluster, or "copper fist", which organizes the protein into a specific DNA binding factor. In support of this model, we have shown that ACE1 binds Cu(I) cooperatively, that the Cu-binding cysteine residues and DNA-binding basic residues are interdigitated within a single domain, and that a purified ACE1 peptide is luminescent. An in vitro transcription system responsive to ACE1 has been developed, and a genetic search for additional metallothionein gene transcription factors has been initiated.